Dry eye is a multifactorial disease of the ocular surface. With the prevalence of dry eye continuing to increase and only two FDA approved drugs available that are effective in only a subset of patients, there is an unmet need for the development of new therapies. Here I propose that butyrate, a short-chain fatty acid (SCFA) and a byproduct of the fermentation of dietary fiber by anaerobic commensal bacteria, is essential in maintaining ocular surface homeostasis. We will test the hypothesis that in homeostasis, normal gut microbial communities have an abundance of different butyrate-producing bacteria, that can ferment dietary fiber and produce SCFA, including butyrate. We will address this hypothesis with 3 aims. Aim #1: to investigate the protective mechanism of action of butyrate on the ocular surface epithelium. I will determine if butyrate signals through its receptors or through its transporter to exert anti-inflammatory actions. Aim #2: to investigate the role of butyrate in the development of ocular surface inflammation and Sjgren Syndrome-like disease in-vivo. I will determine if butyrate signaling through its transporter essential for maintaining ocular homeostasis under stress conditions. To accomplish this, I will modulate the microbiome and expose mice to well-known stressors. Aim #3: to investigate butyrate as a novel therapy for ocular surface diseases. In this aim, I will test if modulation of gut microbiome through diet or supplementation can have a beneficial effect on the ocular surface by promoting SCFA production by commensal bacteria. Overall, these studies aim to explore a novel byproduct of the microbiome that is involved in maintaining ocular surface homeostasis. These data will be invaluable to the field of dry eye and could provide new therapeutic targets.